This application delineates a 5-year program to provide the training toward the development of an independent academic research career in the study of neuron control of glucose homeostasis. The goal of this research program will be to determine brain mechanisms that govern normal physiology and pathophysiology of blood sugars in order to provide molecular targets for therapy. The candidate has been prepared for this pathway by completing a PhD degree involving the study of high-fat diet effects on voluntary activity, leptin signaling, and metabolic disease. Following his PhD, the candidate continued to gain new abilities working as a postdoctoral scientist with a type 1 diabetic model leading to the identification of the ventromedial nucleus of the hypothalamus (VMN) as a critical node requiring energy signals for normalization of diabetic hyperglycemia. The applicant has been very productive through both graduate and postdoctoral work contributing to 21 manuscripts to well respected journals, 8 of them first author. He has successfully competed for fellowships in the past and now seeks a Mentored Research Scientist Award to support ongoing efforts to harness the power of optogenetics to manipulate specific types of neurons to identify those required for glucose balance. Although the pursuit of novel, emergent areas of research entails an inherent degree of risk, this endeavor has already generated fruitful data and continues to provide a valuable training experience. The proposed research will be conducted in the laboratory of Dr. Michael Schwartz and Dr. Gregory Morton, both experts in the field of hypothalamic regulation of energy balance and glucose homeostasis, and will involve collaboration with a large group of experts in metabolism and glucose flux at the University of Washington and Vanderbilt (Dr. David Wasserman). It will be overseen by an expert mentoring committee with two members of the Endocrinology Division (Dr. Steven Kahn and Dr. Joshua Thaler) as well as an external advisor well respected for his research and mentoring capacity (Dr. Martin Myers, University of Michigan). The comprehensive training plan involves continued education in viral targeting techniques and methods for the determination of insulin-dependent and insulin-independent glucose disposal. The work will be presented at national meetings and through scientific publication. Both past and current work implicates the brain in the control of glucose homeostasis yet much about how this control occurs and the pathologies induced by its dysregulation remain unknown The goal of the current work is to identify neurocircuits that control blood glucose and to investigate how they mediate their effects. The application focuses on evidence that hypothalamic VMN neurons play a critical role to regulate glucose balance under physiological settings, and that activation of these neurons results in pathophysiological hyperglycemia and glucose intolerance. Using state-of-the-art optogenetics approaches with cre-dependent channel rhodopsin-expressing virus to exclusively target SF1 neurons within the VMN the preliminary data identify a subset of VMN neurons that, when activated, induce diabetes-range hyperglycemia in otherwise normal mice. This finding supports studies proposed in Specific Aim 1 to determine the mechanisms underlying the effect on glucose homeostasis of VMN neuron activation and its pathophysiological role in diabetic hyperglycemia. Two different approaches will be applied to understand how glucose control is changed, the euglycemic-hyperinsulinemic clamp and frequently sampled intravenous glucose tolerance test. Each method yields information regarding glucose homeostasis that is distinct, complementary, and ultimately required for a full understanding of study outcomes with the former providing evidence for insulin-dependent glucose regulation while the later measures insulin-independent glucose disposal. Additional preliminary data using optogenetics shows that upon activation of the SF1 neuronal projections to the aBNST glucose concentrations are again increased where photo-activation of other SF1 projection sites revealed no change. These findings identify the SF1? aBDNF neuron projections as the first defined hypothalamic neurocircuit capable of driving hyperglycemia and provide a basis to continue characterizing this circuit and determine its relevance in insulin dependent diabetes as proposed in Specific Aim 2. The applicant's combination of expertise in molecular biology, histochemistry, pharmacology, and physiology of the neuronal regulation of food intake and glucose metabolism uniquely qualify him to receive a Mentored Research Scientist Award. With this support, he will address key questions in the field of neurobiology and metabolism, the answers to which will increase our understanding of how the brain regulates glucose homeostasis to establish the basis of an independent career.